A population-based study comparing multiple sclerosis clinic users and non-users in British Columbia, Canada.

BACKGROUND AND PURPOSE: Much clinical knowledge about multiple sclerosis (MS) has been gained from patients who attend MS specialty clinics. However, there is limited information about whether these patients are representative of the wider MS population. The objective of this study was to compare incident MS cases who were MS clinic users to non-users of the specialty MS clinics in British Columbia, Canada. METHODS: This was a retrospective record-linkage cohort study using prospectively collected data from the British Columbia Multiple Sclerosis database and province-wide health administrative databases. RESULTS: There were 2841 incident MS cases between 1996 and 2004 including 1648 (58%) that had registered at an MS clinic ('clinic cases') and 1193 (42%) that had not ('non-clinic cases'). Gender and socioeconomic status distributions were similar; however, non-clinic cases were older, accessed health services more frequently and had a higher burden of comorbidity than clinic cases. Only 1% of the non-clinic cases had filled a prescription for an MS-specific disease-modifying therapy, compared to 51% of the clinic cases. CONCLUSIONS: Our findings have several important implications: even within a publicly funded healthcare system, a high proportion of individuals with MS may not access a specialty MS clinic; the needs of MS patients managed in the community may differ from those referred to an MS clinic; findings from studies involving clinic-based MS cohorts may not always be generalizable to the wider MS population; and access to population-based health administrative data offers the opportunity to gain a broader understanding of MS.

Cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1) in cultured human oligodendrocytes and astrocytes.

We investigated the expression of intercellular adhesion molecule-1 (ICAM-1) on primary cultures of human adult oligodendrocytes and astrocytes. Under unstimulated conditions, low levels of ICAM-1 immunoreactivity were identified on both oligodendrocytes (less than 50%) and astrocytes (less than 30%). After 48 hours' exposure to immune mediators, such as culture supernatant of phytohemagglutinin (PHA)-stimulated lymphocytes, interferon gamma (IFN-gamma; 1,000 U/ml), tumor necrosis factor alpha (TNF-alpha; 2,000 U/ml), interleukin-1 alpha (IL-1 alpha; 1,000 U/ml) and lipopolysaccharide (LPS; 50 micrograms/ml), ICAM-1 expression on both cell types was markedly increased in terms of intensity and cell numbers. IFN-gamma and culture supernatant of PHA-stimulated lymphocytes were the most potent inducers of ICAM-1 among the mediators tested, while TNF-alpha, IL-alpha and LPS were less effective, although variations were observed among cultures derived from different donors. Cytokine-induced expression of ICAM-1 on glial cells may play a role in mediating lymphocyte-glial cell interactions at sites of inflammation in the central nervous system.

Herpes simplex virus type I (HSV I)-induced multifocal central nervous system (CNS) demyelination in mice.

Multifocal central nervous system (CNS) demyelination develops in the brains of SJL/J, PL/J, and A/J mice following lip inoculation with a specific strain of herpes simplex virus I (HSV I). The lesions in all three inbred strains of mice share similar characteristics including demyelination, relative preservation of axons, and a mononuclear cell (MNC) infiltrate. The lesions, developing during the early phase of demyelination, also appear sequentially in the CNS (trigeminal root entry zone of the brainstem greater than cerebellum greater than cerebral hemispheres) of all three strains of mice but differ in the time of their initial appearance following infection as well as their morphology. In SJL/J mice, new areas of demyelination are observed for only 24 days following lip inoculation with virus. Late stage multifocal CNS demyelination persists throughout 28 weeks postinoculation (pi) in PL/J mice while in A/J mice the development of new areas of demyelination are restricted to 8 weeks pi. Although mononuclear inflammatory cells are present in the new areas of demyelination in either PL/J or A/J mice, viral antigens are not detected in the CNS beyond 12 days pi. In contrast, in situ hybridization studies using 35S-cDNA HSV probes and performed beyond day 12 pi identify probe-positive cells central to a number of the multifocal CNS demyelinating lesions in A/J mice. Results from studies with inbred and congenic strains of mice indicate that the major histocompatibility complex (H-2) does not determine the development of multifocal CNS demyelination following lip inoculation with HSV I but does influence the morphological appearance of the lesions that do develop.

Pregnancy and multiple sclerosis. A prospective study.

OBJECTIVE: To conduct a prospective assessment of pregnancy on women with multiple sclerosis (MS), focusing on pregnancy outcome and relapses during gestation and up to 6 months after delivery. DESIGN: Expected numbers of relapses were based on data for (1) "self-controls": the mothers ("cases") themselves prior to becoming pregnant and (2) "matched controls": female patients with MS "matched" to the mothers for year of birth, age of MS onset, MS type, MS course, and initial MS symptom(s). SETTING: Cases and controls were identified from an ambulatory care MS clinic that serves the province of British Columbia, Canada. PATIENTS OR OTHER PARTICIPANTS: Women with a diagnosis of MS who attended the MS clinic during 1982 through 1986 and subsequently became pregnant during 1982 through 1989 inclusive were included in this study as cases. Matched controls were women with MS who attended the MS clinic during the same period but did not become pregnant. RESULTS: No significant increase in relapse rate was found for cases during the first two trimesters of gestation. The number of relapses was significantly less than expected during the third trimester compared with matched controls (chi 2 = 6.80, df = 1, P < .02), but not compared with self-controls (chi 2 = 3.39, df = 1, P > .05). The observed number of relapses for the 6 months after delivery did not differ significantly from expected (self-controls: chi 2 = 2.84, df = 2, P > .05; matched controls: chi 2 = 1.76, df = 2, P > .05). CONCLUSION: These data suggest that neither pregnancy nor the 6-month period after delivery is a risk factor for relapse in MS. They are consistent with previous observations that, in the long term, pregnancy does not influence subsequent MS disability.

Multiple sclerosis: in relapsing patients, immune functions vary with disease activity as assessed by MRI.

We have serially studied immunoglobulin G secretion in vitro, natural killer cell function, and concanavalin A-induced suppression in a group of seven patients with relapsing-remitting multiple sclerosis. In two patients, the development of a large clinically asymptomatic MRI lesion was accompanied by reductions in natural killer cell function, immunoglobulin G secretion in vitro (after pokeweed mitogen stimulation), and concanavalin A-induced suppression without parallel change in lymphocyte markers. We did not see this type of change in matched controls nor in stable multiple sclerosis studied serially. When clinical attacks appeared, there was no significant change in immune function. We conclude that changes in immune function correlate well with the activity of the disease as recognized by MRI. We suspect that decreased natural killer cell function, immunoglobulin G secretion in vitro, and concanavalin A-induced suppression are secondary to the large lesions recognized by MRI.

Multiple sclerosis: a serial study using MRI in relapsing patients.

Prospective monthly magnetic resonance imaging (MRI) studies were done over 6 months in seven relapsing MS patients. MRI and neurologic evaluations were compared for sensitivity in detecting disease activity. Four patients were clinically stable throughout the study. Three patients had five clinical relapses, two localized to the spinal cord and three to the brainstem. Eighteen new and ten enlarging MRI lesions were seen in five patients. Most lesions were less than 10 mm in diameter. All were clinically silent. Two patients developed major enlarging MRI lesions (seen in three slices) which increased in size over 2 months and then gradually became smaller over 2 months, leaving behind small residual areas of abnormality. There were 36 follow-up scans, 17 of which (47%) showed evidence for increasing activity. Thirteen (36%) of the scans had new lesions, most of them being small. This study shows that MRI evidence for disease activity in MS is much more frequent than is clinical evidence.

Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: a prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT.

We previously compared the diagnostic capabilities of MRI of the head with CT, evoked potentials, and CSF oligoclonal banding (OB) analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). To examine the ability of MRI and other paraclinical tests to predict the diagnosis of clinically definite MS (CDMS), we did a systematic clinical follow-up of 200 patients who were previously reported. In that study, 85 of 200 could be diagnosed as having laboratory-supported definite MS (LSDMS). In follow-up, we excluded one patient diagnosed as LSDMS who in retrospect was considered to have had CDMS at entry and 15 patients who were eventually diagnosed as having other diseases. After a mean follow-up of 2.1 years, 55 of the remaining 184 patients (30%) had developed CDMS. Thirty-eight of 84 patients with an original diagnosis of LSDMS (45%) and 17 of the remaining 100 patients with suspected MS (17%) had become CDMS. Forty-six of the 55 patients who developed CDMS in follow-up (84%) had an initial MRI that was strongly suggestive of MS. Fifty-two of those 55 CDMS patients (95%) had at least one MS-like abnormality on MRI when originally studied. In contrast, 38 of 55 (69%) had CSF OB, 38 of 55 (69%) had an abnormal VEP, 35 of 55 (64%) had an abnormal SEP, and 21 of 55 (38%) had an abnormal CT when first studied. MRI was the most sensitive single paraclinical test for predicting CDMS. CDMS developed during follow-up in 46 of the 94 patients (49%) whose initial MRI was strongly suggestive of MS.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. II. Immunologic evaluation.

Immunologic functions are studied in conjunction with a placebo-controlled trial of lymphoblastoid interferon (IFN) in patients with chronic progressive (CP) multiple sclerosis. Prior to treatment, CD4+ cells are significantly increased and CD8+ cells decreased in the blood of MS patients. Both CD5+ and CD4+ cells increase significantly with IFN therapy early during the treatment phase of the trial, while the number of CD8+ cells decreases steadily, becoming significant at 6 months. CNS IgG synthesis rates increase with IFN treatment and maximize at 3 months. Serum antiviral activity also increases with IFN treatment. In the IFN-treated group, a trend toward improvement, determined clinically and by MRI, likely reflects the influence of a subpopulation of 10 patients. This subpopulation is now further characterized by an early increase in CNS IgG synthesis and numbers of CD5+ cells in the blood. Although these immune functions may identify a number of CP MS patients who might benefit from IFN, it is unlikely that these mechanisms actually mediate the potentially beneficial effects of this cytokine.

Natural killer cells in relapsing-remitting MS: effect of treatment with interferon beta-1B.

OBJECTIVE: To determine the effect of treatment with interferon beta-1b (IFN-beta) on natural killer (NK) cell function and phenotype in relapsing-remitting MS (RRMS) patients, and their relationship to disease activity assessed both clinically and with serial MRI. BACKGROUND: NK cells may play a role in the immunopathogenesis of MS. Previously the authors reported a positive relationship between mean NK cell functional activity (FA) and total number of active lesions on MRI in a serial study of RRMS. Cycles in NK cell FA over time created a series of peaks and valleys, and a significant relationship has been identified between the valleys and the appearance of active lesions on MRI or onset of clinical attacks. The development of valleys in NK cell FA before the appearance of active lesions on MRI was statistically significant. METHODS: The authors studied the effect of alternate-day therapy with 8.0 mIU (high dose [HD]) or 1.6 mIU (low dose [LD]) IFN-beta on NK cell FA, assessed by an in vitro 51Cr release K-562 target cell assay, and phenotype determination in RRMS patients. RESULTS: Treatment with HD IFN-beta results in an inverse relationship between mean NK cell FA and total number of active lesions on MRI over 2 years. A stronger inverse relationship was found in those patients who did not develop neutralizing antibodies to IFN (HD-) compared with a positive relationship in those who did (HD +). Treatment with IFN-beta did not affect the cyclic nature of NK cell FA, mean NK cell FA, variability around the mean, mean length of the cycle, time spent in valleys and peaks, or the significant relationship between the appearance of active lesions on MRI/onset of clinical attacks and valleys in NK cell FA. In contrast, treatment with HD but not LD IFN-beta did result in a significant reduction in CD57+ (a cell surface marker for subsets of NK cells) peripheral blood lymphocytes (PBL) compared with placebo. This effect, which originated largely from the HD- group of patients, developed shortly after treatment was initiated and was maintained throughout the study. CONCLUSIONS: RRMS patients with higher mean NK cell FA may be not only at greater risk for the development of active lesions but also may be more likely to respond to IFN-beta. Development of neutralizing antibodies to IFN-beta could interfere with this effect. This effect may be mediated through an action on a CD57+ subset of PBL.

MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT.

We compared the diagnostic capabilities of MRI to CT, evoked potentials (EP), and CSF oligoclonal banding analysis in a prospective evaluation of 200 patients with suspected multiple sclerosis (MS). MRI was the best method for demonstrating dissemination in space. An abnormal appropriate EP in monosymptomatic disease was usually supported by MRI and CSF analysis as being predictive of MS as a clinical diagnosis. A normal appropriate EP study was not satisfactory because MRI and CSF analysis often did not support a diagnosis of non-MS. When there is agreement between three of these paraclinical studies, the diagnosis of MS is probably unequivocal. For use in research studies, laboratory-supported definite MS (LSDMS) could be diagnosed in 85 patients of the total 200 (42.5%), in 19/38 (50%) of optic neuritis (ON) patients, and in 24/52 (46%) of chronic progressive myelopathy (CPM) patients. MRI was 100% successful in identifying patients who qualified for LSDMS in the ON and CPM groups. In a short follow-up (less than 1 year), 19/200 (10%) went on to develop clinically definite MS (CDMS), and MRI predicted that diagnosis in 18/19 (95%). Only long-term follow-up will show how well these studies and the category of LSDMS predict the development of CDMS. The clinical diagnosis of MS (CDMS), even though only 95% accurate, must remain the gold standard.

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. I. Clinical and MRI evaluation.

A randomized, double-blind, placebo-controlled, noncrossover trial determined the efficacy of lymphoblastoid interferon (IFN) in chronic progressive multiple sclerosis (CP MS). Fifty patients received 5 X 10(6) IU IFN subcutaneously daily for 6 months while 50 received placebo. After 2 years, there were no significant differences between the 2 groups based on clinical evaluations and quantitative MRI analysis of the brain, although a trend was observed in the IFN group. Clinically, the IFN group was worse at 1 and 3 months and improved at 6 to 18 months, when compared with the placebo group. Results of MRI evaluations of the brain at 6 months support this trend. This trend likely resulted from a subpopulation of 10 IFN-treated patients, characterized by a higher women:men ratio and a lower EDSS score at entry into the trial. We cannot recommend lymphoblastoid IFN as treatment for CP MS at this time.

Depression and multiple sclerosis.

The objective of the present study were (1) to ascertain the lifetime risk of a depression in a representative group of multiple sclerosis (MS) patients, (2) to assess the morbidity risks for depression among first-degree relatives of these MS patients, and (3) to compare these familial risks for first-degree relatives of MS patients with those for first-degree relatives of a primary depression population, i.e., depression but no MS. We psychiatrically evaluated 221 MS patients (index cases) using a structured clinical interview for the DSM-III-R and calculated the rate and lifetime risk of depression for these index cases using the product limit estimate of survival function. We obtained psychiatric histories for all first-degree relatives of index cases, and we calculated morbidity risks for depression for these relatives using the maximum likelihood approach and compared the risks using the likelihood ratio tests. Index cases had a 50.3% lifetime risk of depression. Morbidity risks for depression among first-degree relatives of index cases were decidedly lower when compared with morbidity risks among first-degree relatives of the reference population. Although there appears to be a very high rate of depression among MS patients, the data for their first-degree relatives do not support a clear genetic basis for this depression, or at least the same genetic basis that probably operates within families when depression occurs in the absence of MS.

A two-label microfluorometric analysis of the expression of OKT5 and Leu 2a antigens on peripheral blood lymphocytes in patients with multiple sclerosis.

Four patients with relapsing-remitting multiple sclerosis (MS) and one control were evaluated serially over a 10-week interval. Peripheral blood lymphocyte (PBL) subsets were enumerated using a double labelling technique, OKT5 and anti-Leu 2a monoclonal antibodies, and FACS IV analysis. Results were correlated with clinically assessed disease activity. Two subsets were identified. Subset 1 is characterized by cells positive for Leu 2a and either weakly positive or negative for OKT5 . Subset 2 was positive for both. Subset 1 was constantly present in both patients and controls while subset 2 was variable in presence and in size. No associations between these subsets and disease activity were made in this preliminary study, however, no acute relapses occurred in this interval. It is postulated that the reason for the differences in results of studies attempting to correlate disease activity with PBL phenotypes as assessed by different monoclonal antibodies may be the result of the suppressor/cytotoxic cell subpopulation being nonhomogeneous for the expression of various cell surface antigens. The technique of multiple labelling of lymphocytes may be useful in defining subsets which correlate more closely with disease activity.

Cytolysis of oligodendrocytes is mediated by killer (K) cells but not by natural killer (NK) cells.

The cytotoxic activity of killer (K) cells against enriched cultures of bovine oligodendrocytes (BOL) was investigated in multiple sclerosis (MS) and controls. Human K cells mediated cytotoxicity to primary cultures of BOL in the presence of anti-BOL antiserum in all study groups, while BOL were resistant to human natural killer (NK) cells. Cytotoxic activity was significantly reduced in MS when compared to age-matched normal controls but not when compared to other neurologic disease (OND) patients. K cell-mediated lysis of BOL could also be induced with anti-galactocerebroside antibody but not with other antibodies including those specific for OL antigens (myelin basic protein, proteolipid apoprotein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase). Enrichment of the effector population indicated that antibody-dependent cell-mediated cytotoxicity (ADCC) to BOL was mediated by large granular lymphocytes, and the effector population was further characterized by flow cytometry. The effector cells mediating ADCC could be inhibited by protein A of Staphylococcus aureus, and by K562 cells in cold competition assay. These observations indicate that oligodendrocytes are resistant to NK cells but are susceptible to cytolysis mediated by K cells. This may represent a potentially important immune mechanism in the pathogenesis of MS.

Absence of natural killer (NK) cell activity against oligodendrocytes in multiple sclerosis.

The cytotoxicity of natural killer (NK) cells directed to enriched cultures of bovine oligodendrocytes was investigated in multiple sclerosis (MS) patients and controls. Macrophage-depleted peripheral blood lymphocytes were used as effector cells in a 4-h 51Cr release assay. No significant cytotoxic activity to oligodendrocytes was identified in either MS or control groups. In contrast, a definite cytotoxic activity directed toward K562 cells was observed in the study populations. No statistically significant difference was observed between chronic progressive or stable MS, other neurological diseases (OND), and normal controls. These results indicate that NK cell activity directed toward intact bovine oligodendrocytes is not significantly different between MS and control groups and question the significance of studies employing K562 cells as the target in NK assays in MS. Furthermore, these observations suggest that NK-mediated cytotoxicity against oligodendrocytes is unlikely to be a specific mechanism mediating demyelination in MS.

Lymphokine-activated killer (LAK) and adherent LAK (A-LAK) activity in multiple sclerosis.

The cytotoxic activity of lymphokine-activated killer (LAK) cells against enriched cultures of oligodendrocytes (OL) was investigated in multiple sclerosis (MS) and controls. Human LAK cells, derived from macrophage-depleted peripheral blood mononuclear cells (PBMC) and incubated with recombinant human interleukin-2 (IL-2) (20-80 U/ml), mediated high levels of cytotoxicity against Raji cells but low levels of cytotoxicity against primary cultures of bovine OL. Cytotoxicity was not enhanced by incubation with a high level of IL-2 (500 U/ml). No statistically significant differences in LAK cell activity against bovine OL were observed among the study groups. Enriched adherent LAK (A-LAK) cells mediated greater levels of cytotoxicity against both bovine OL and tumor cell lines than unfractionated LAK cells. Flow cytometric analysis indicated that A-LAK effector cells were CD4-, CD8+, and CD16+. Furthermore, A-LAK cells mediated lysis of OL derived from several different animal species. Our results suggest that LAK and A-LAK cells can mediate cytolysis of OL in culture similar to that observed with a number of different tumor cell lines. However, no significant difference in cytolysis was identified between MS and control groups in this study.

Progressive multiple sclerosis: abnormal immune functions in vitro and aberrant correlation with enumeration of lymphocyte subpopulations.

In a series of 27 consecutive progressive multiple sclerosis (MS) patients under age 50 we have simultaneously measured 3 in vitro immune functions and 6 markers and compared their results to a group of 21 controls. We have confirmed a reduction of concanavalin A (Con A) -induced suppression and NK function contrasting with increased IgG secretion in response to pokeweed mitogen (PWM). Among 6 monoclonal antibody-recognized subpopulation (Leu 1, Leu 2, OKT8, Leu 3, Leu 7 and Leu 11) only Leu 2+ lymphocytes were statistically reduced. OKT8+ were slightly reduced, Leu 3+ were slightly increased. Discriminant analysis revealed that the 3 immune functions together with the results of OKT8 and Leu 3 enumeration were sufficient to appropriately classify most of the individuals. Only 3 MS and 4 controls were misclassified. Correlation analysis suggested disappearance of the doubly labelled OKT8/Leu 7 population in MS patients. In MS as opposed to controls Con A-induced suppression did not correlate with suppressor cell markers but correlated with NK cell markers suggesting that in MS this population mediates Con A-induced suppression. IgG secretion and Con A suppressor cell function were inversely correlated in MS patients but not in controls, suggesting that in chronic progressive multiple sclerosis a common abnormality underlies both increased response to PWM and decreased induction of suppression by Con A.

Natural killer (NK) cells in chronic progressive multiple sclerosis patients treated with lymphoblastoid interferon.

Natural killer (NK) cell functional activity, as defined by the lysis of 51Cr-labelled K-562 cells, and number, defined phenotypically by anti-Leu-11, are significantly decreased in chronic progressive multiple sclerosis (MS) when compared to normal controls. When age- and sex-matched populations are compared, NK cell functional activity is again significantly reduced in MS compared to controls but not when compared to a control group of other medical disease (OMD). The MS group could be differentiated from the OMD group, however, when results of NK cell functional activity are combined with NK cell phenotype. With the administration of lymphoblastoid interferon daily for 6 months, NK cell activity increased significantly at 48 h and at 1 week. By 1 month, activity decreased to a level slightly above placebo treatment values. The results likely reflect interferon's enhancement of mature NK cell activity combined with a variable effect on recruitment of pre-NK cells.

Central nervous system infection and immune response in mice inoculated into the lip with herpes simplex virus type 1.

Virus may be recovered from various areas of the central nervous system (CNS) of mice for as long as 11 days after inoculation of herpes simplex virus type 1 (HSV-1) into the lip. The probability of isolation from any particular region of the CNS seems to be a function of the distance of that area from the root-entry zone of the trigeminal nerve. It is also mouse strain-dependent, with much more extensive evidence of brain infection being found in BALB/c and C3H rather than C57BL/6 mice, in which it is limited to the pons. The virus could not be isolated from the CNS of BALB/c mice after 10 days, though HSV-1 is readily recovered from the trigeminal ganglia at least through day 38. Significant concentrations of HSV-1-specific immunoglobulin (Ig) were demonstrated consistently in cerebrospinal fluid (CSF) from day 12 after exposure to virus. The persistence of relatively high concentrations of IgM in the CSF indicates that much of this antibody may be synthesized locally in the brain.

A role for natural killer cells in the immunopathogenesis of multiple sclerosis.

Seventeen relapsing-remitting (R/R) multiple sclerosis (MS) patients and age/sex matched controls were studied every 6 weeks for 2 years. Disease activity, determined both clinically and by serial MRI, was correlated with natural killer (NK) cell functional activity (FA) and phenotype. Mean NK cell FA is significantly lower in MS patients, compared to controls (P < 0.001), while variability around the means is significantly greater (P < 0.01). The spectrum of mean NK cell FA, observed in the patient cohort, along with cyclical nature of the FA and phenotype over time, observed in both patients and controls, may begin to explain the discrepant results reported in previous studies. In R/R MS, there is a significant correlation between reductions (valleys) in NK cell FA and the development of active lesions on MRI, new (P < 0.001) or enlarging (P = 0.05). More importantly, a significant number of active lesions, new (P = 0.01) and enlarging (P = 0.02), are preceded by a reduction in NK cell FA. The correlation between the onset of clinical attacks and valleys of NK cell FA is also significant (P = 0.002). When taken together, the results suggest that reductions (valleys) in NK cell FA represent periods of susceptibility for the development of active lesions on MRI and clinical attacks. A significant positive correlation is also identified between mean NK cell FA for each R/R MS patient and total number of active MRI lesions developed by that patient over the 2 years (P = 0.001). The results would suggest that R/R MS patients with a higher mean NK cell FA are at greater risk for the development of active lesions. These results support the proposal that NK cells may play a role in the immunopathogenesis of R/R MS.